Acylated thiol esters from etiobilienic acid esters



Patented Feb. 19, 1952 UNITED STATES ATENT OFFICE ACYLATED THIOL ESTERS FROM ETIOBILIENIC ACID ESTERS Gordon A. Grant, Montreal, Quebec, and Carl von Seemann, Westmount, Quebec, Canada, assignors to Ayerst, McKenna & Harrison, Limited, Montreal, Quebec, Canada, a corporation of Canada No Drawing. Original application April 1, 1948, Serial No. 18,485. Divided and this application March 2, 1950, Serial No. 147,324. In Canada December 22, 1947 This application is a division of copending application Serial No. 18,485, filed by Gordon A.

Grant and Carl von Seemann April 1, 1948, for Lactones from Etiobilienic Acid, now Patent No.

INTRODUCTION The present invention relates to new alkylthiol esters of 3(6) acyletiobilienic acid monoalkyl esters. These compounds have potential value in organic syntheses, as in the synthesis CH3 CH3 CHaCOOH monoalkyl esters of camphoric acid, denoting the esters obtained by acid alkylation of the free acid as the a-esters, and those obtained by partial hydrolysis of the dialkylesters as the fi-esters. Both aand B-esters were prepared by Kuwada, as was also the acetate of the c-methylester.

In the course of his work on l6-hydroxytestosterone, Butenandt (Ber. d. Deutsch. Chem. Ges. 72(3), 417 (1939)) isolated A -3-( 3)-acetoxy-etiobilienic acid as well as its anhydride,

using transdehydroandrosterone (T. D. A.) or its I acetate as the starting material.

Wettstein and his collaborators (Helvetica Chim. Acta 24, 332E (l 941) a'oplying their method of oxidation with potassium hypoiodite to T. D. A.-acetate, obtained the anhydride of A ,QS-(fi) -acetoxy-etiobilienic acid as the main prod- 3 Claims. (Cl. 260-455) uct, and the corresponding dimethylester-acetate as a by-product of their reaction.

THE APPLICANTS DEVELOPNEENT The applicants have now found that new compounds can be derived from the aand ,8- monoalkylesters of A -3-(p)-hydroxy-etiobilienic acid having the general formula CmHzaOsand believed to be one or other of two different lactones and thought to have the following respective formulae:

CHr-CH:

CH: CH!

CH:O

The procedure of the applicants invention involves the following steps when starting with a.- and p-mono-alkylesters of A -3-(fl) -hydroxyetiobilienic acid, preferably having not more than three carbon atoms in the mono-alkyl group, for example the monomethylesters. I 1. Protection of the B-hydroxy group of the mono-alkylester of A -3-(p)-hydroxy-etiobillenic acid by acylation. Protection is preferably accomplished by acylating with a common acylating agent, for example acetic, propionic or butyric anhydride in a solution in a solvent, desirably pyridine.

2. Reaction of the acylated compound obtained as above with a mild halogenating agent to yield the 3-acylated mono-alkylester acid halide, the halogenating agent being preferably oxalyl' chloride or thionyl chloride.

3. Reaction of the acid halide obtained as above with a mono functional mercaptan, preferably methylor benzyl mercaptanto yield the B-acylated alkyl thiol ester.

4. Treatment of the 3-acylated alkyl thiol ester with Raney nickel under the conditions described by Jeger and his collaborators (Helv. Chim. Acta 29, 684 (1946)) whereby the thiol 5. Hydrolysis of the acylated lactone to the lactone C19H2803.

The following flow-sheet shows the. .general.

course of the reactions involved in the preparation of the lactones CmH-zaOa.

CH: 0 H; OH CH1 s C O O CH:

CHzG 0 0H AcO Steps I 1 andi2 i II C O O CH:

CHiC 0 C] III Step 3 IV CQHQGHZSH CeHiCHzSHK pyridine pyridine CH! CH CH! CH;

000011, eoscmcom GHnCOSCHiCuHI CHz'COOCHi' A00 A00 Q V Step 4 VI lRaney nickel lRar cy nickel on, C Cm CH;

/0 CHaCHi AcO A00 VII Step 5 VIII? 1 Hydrolysis: lHydrolysis.

CH: CH; CH," CHaZ C=O- CH?--0T' CHzG=O CHJCH! EXAMPLES Kuwada'; loo; cit.) 6.6 g. is dissolved in 100 cc.

examples are illustrative-only and not to' be taken as, limiting.

4 Example 1.-Prepamtion of the fi-lactone IX (Zactoneof N -2,1 3-dimethyl-1 -hydro:vyethyl- 7(5) hydromydodecahydrophenanthryl 2- carbozzylz'c acid) STEPS 1 AND 2.-3-ACETOXY-A5'-ETIOBILIEN'I C Mien) CHLORIDE B-MONOMETHYLESTER In The 3.-acetoxy-A -etiobilienic acid p-monomethylester (I) obtained by acetylation of the freecompound in the usual manner (see also 70 dry benzene and 12.5 cc. oxalyl chloride are added. When the violent reaction has subsided; the

mixture is kept at 6575C. forlfi'minutes and then evaporated to dryness in vacuo. The resivacuo.

anol.

-75 C. for 30 minutes and then evaporated in Traces of oxalyl chloride are then removed by repeated addition of 25 cc. portions of benzene, each portion being removed in vacuo. The residual acid chloride III (7.21 g.) is placed in a desiccator at high vacuum and allowed to crystallize. It is used for subsequent reactions without further purification.

The acid chloride III obtained as in Steps 1 and 2 (7.21 g.) is dissolved in 125 cc. benzene, 10.5 cc. benzyl mercaptan and 2.2 cc. pyridine are added, and the mixture is allowed to stand at room temperature for two days. It is then taken up in 1 litre ether, washed with water, 0.5 N sodium hydroxide, 0.5 N sulphuric acid, and finally again with water until neutral. Evaporation after drying yields the crude 3-acetoxy-A etiobilienic acid a-thiolbenzyl-p-methylester V in yield. It is purified by recrystallization from methanol. One such product gave M. P. 111-111.5 C. ((1) 57.0 in methanol. Calc. for C29H3sO5S: C, 69.85%; H, 7.68%; S, 6.43%. Found: C, 68.42, 68.46%; H, 7.28, 7.21%; S, 6.28, 6.21%.

STEP 4.LA-CTO'NE OF A 2,13 DIMETHYL-l-HY- DROXYETHYL 7 (B) ACETOXY DODECAHYDRO- PHENANTHRYL-2-CARBOXYLIC ACID VII The thiolbenzyl ester V obtained as in Step 3 (1 g.) is dissolved in cc. methanol and stirred for 3 hours with about 10 g. Raney nickel at room temperature. The catalyst is centrifuged 01f and repeatedly washed with 100 cc. portions of methanol. The methanolic extracts are combined, filtered and evaporated in vacuo, giving a practically theoretical yield of the acetoxy-lactone VII, which is purified by recrystallization from meth- One such product gave M. P. 185-187 0., (00 73.7 (in CHCls). Calc. for C21H3004I C, 72.88%; H, 8.74%. Found: C, 72.93, 72.97%; H, 8.96, 8.78%.

The test for the presence of a double bond with tetranitromethane is positive, and the compound upon treatment with 1 mole bromine in glacial acetic acid yields a dibromide, M. P. 153-154 C. Calc. for C21H3004B12! Br, 31.57%. Found: Br. 31.64, 31.70%

STEP 5. LACTONE OF 13 -213-EDIMETHYL-1-HY- DROXYETHYL 7(B)HYDROXY DODECAHYDRO- PHENANTHRYL-Z CARBOXYLIC ACID IX The acetoxy lactone VII as obtained in Step 4 (580 mg.) is refluxed for 2 hours with 40 cc. 1 N potassium hydroxide in 90% methanol, the mixture diluted with ice water, extracted with ether to remove impurities, acidified, extracted with ether, the ether washed, dried and evaporated. After repeated recrystallization from aqueous methanol there are obtained 385 mg. of the lactone IX. One such product gave M. P. 204- 206" C., (11), 56.5 (in methanol). Calc. for Ciel-1280s: C, 74.94%; H, 9.28%. Found: C, 74.82, 75.11%; H, 9.02, 9.22%.

Hydrolysis may also be carried out by refluxing VII in l N aqueous sodium hydroxide, in which it is insoluble in the cold, but goes slowly in solution upon heating, yielding a product identical in every respect with IX. Acetylation of IX in the usual manner yields the acetoxylactone VII.

Example 2.II. Preparation of the a-ltZCtOfi X (lactone of A -2,'13-dimethyZ 2 hydrozcymethyl 7(5) hydroary dodecahydrophenanthrill-1 -acetic acid) STEPS 1 AND 2.3-ACETOXY-A--ETIO'BILIENIC ACID-a-METHYLESTER-B-ACID CHLORIDE IV The a-methylester-3-acetate II as obtained by STEP -3.3-ACETOXY-A ETIO'B'ILIENIC A'CID u-METHYLESTER-B-THIOLBENZYLE'STER VI The acid chloride IV as obtained in the previous Steps 1 and 2 (9.6 g.) is dissolved in cc. benzene, 13.4 cc. benzyl mercaptan and 2.75 cc. pyridine are added and the mixture is allowed to stand at room temperature for 2 days. Working up as previously described in Example Step 3, yields 10.1 g. VI as an oil.

STEP 4. LACTO'NE OF A- -2,'13-DI'METHYL-2HY- 'DROXYMETHYL 7(B)ACETOXY DO DECAHYDRO- PHENANTHRYL-l-ACETIC ACID "III The crude a-methyl-fl-thiolbenzylester acetate VI as obtained in Step 3 (1.63 g.) is dissolved in 150 cc. methanol and stirred at room temperature with about 17 g. Raney nickel for 5 hours. The mixture is worked up as previously described in Step 4 of Example 1, the methanolic filtrates and washings yielding 82% of the crude lactoneacetate VIII, which may be used as such for the subsequent hydrolysis or purified by recrystallization from aqueous methanol. One such lactoneacetate VIII had M. P. 175.5-176 C. (ll) 132.2 (in methanol) and gave a positive test for the presence of a double bond with tetranitromethane. Calc. for C21H30O42 C, 72.88%; H, 8.74%. Found: C, 72.56, 72.57%; H, 9.02, 8.70%.

The lactone-acetate VIII obtained as in the previous Step 4 (0.92 g.) is refluxed 1 hour with cc. 1 N potassium hydroxide in 95% methanol and the mixture worked up as previously described in Step 5 of Example 1. The crude lactone X thus obtained is purified by repeated crystallization from aqueous methanol, yielding 542 mg. lactone X. One such product gave M. P. 199.5-202 C. (D 89.6 (in methanol). Calc. for C19H28O32 C, 74.94%; H, 9.28%. Found: C, 74.69, 74.67%; H, 9.69, 9.48%. The compound gives a strong depression of the melting point when mixed with the lactone IX obtained according to Step 5 of Example 1. Hydrolysis may also be carried out by refluxing VIII in 1 N aqueous sodium hydroxide, in which the compound is insoluble in the cold, but goes slowly in solution upon heating, yielding a product identical in every respect with X. Acetylation of X in the normal manner yields the acetoxy-lactone VIII.

We claim:

1. An alkyl-thiol ester of a 3(,8)-acyletiobilienic acid alkyl ester.

2. 3(5) -aoetoxy-A -etiobi1ienic acid fi-methylester-a-thiolbenzyl-ester.

3. 3(5) -acetoxy-A -etiobilienic acid a-methylester-fl-thiolbenzyl-ester.

GORDON A. GRANT. CARL VON SEEMANN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,494,253 Mieschner et al. Jan. 10, 1950 2,508,786 Grant et a1 May 23, 1950 2,509,171 Ruzicka et a1. May 23, 1950 

1. AN ALKYL-THIOL ESTER OF A 3(B)-ACYLETIOBILIENIC ACID ALKYL ESTER. 